What are the alternatives to statins (HMG-CoA reductase inhibitors) for decreasing low-density lipoprotein (LDL) levels?

Alternatives to Statins for LDL Reduction

For patients who cannot tolerate statins or need additional LDL-lowering beyond statins, ezetimibe is the first-line alternative due to its proven cardiovascular benefit, safety profile, and modest LDL-C reduction of 15-20%. 1, 2

First-Line Alternative to Statins

Ezetimibe

• Mechanism: Selectively inhibits cholesterol absorption in the small intestine by blocking the Niemann-Pick C1-like 1 (NPC1L1) transporter 1, 3
• Efficacy: Reduces LDL-C by 15-20% as monotherapy 2, 3
• Dosing: 10 mg orally once daily, with or without food 2
• Cardiovascular benefit: Demonstrated 7% relative risk reduction in cardiovascular events when added to statin therapy in the IMPROVE-IT trial 4
• Safety profile: Similar to placebo when used as monotherapy 2, 3
• Best for: Statin-intolerant patients or those needing additional LDL-C reduction 1, 5

Second-Line Alternatives

PCSK9 Inhibitors

• Examples: Evolocumab, alirocumab, inclisiran (siRNA) 6
• Mechanism: Increase LDL receptor availability by inhibiting PCSK9 protein 6
• Efficacy: Reduce LDL-C by 50-60% beyond statin therapy 6
• Cardiovascular benefit: 15-20% relative risk reduction in major adverse cardiovascular events 6
• Administration: Subcutaneous injections every 2-4 weeks (evolocumab, alirocumab) or twice yearly (inclisiran) 6
• Best for: Patients with very high cardiovascular risk not achieving goals with statin + ezetimibe 6

Bile Acid Sequestrants

• Examples: Cholestyramine, colestipol, colesevelam 6, 1
• Mechanism: Bind bile acids in intestine, preventing reabsorption and increasing cholesterol excretion 1
• Efficacy: Reduce LDL-C by 18-25% 6, 1
• Cardiovascular benefit: ~20% CVD risk reduction in primary prevention 1
• Administration: Must be taken ≥2 hours before or ≥4 hours after ezetimibe if used in combination 2
• Limitations: Gastrointestinal side effects, drug interactions 3

Bempedoic Acid

• Mechanism: Inhibits ATP citrate lyase, reducing cholesterol synthesis 6
• Efficacy: Reduces LDL-C by approximately 15-25%
• Best for: Patients with diabetes/metabolic disorders who are statin-intolerant 6
• Advantage: May help optimize both LDL-C therapy and glycemic control 6

Other Options

Fibrates

• Examples: Fenofibrate, gemfibrozil 6
• Primary effect: Reduce triglycerides and increase HDL-C
• LDL-C effect: Variable, modest reduction
• Best for: Patients with mixed dyslipidemia (elevated LDL-C and triglycerides) 6
• Combination use: Ezetimibe can be used in combination with fenofibrate 2

Icosapent Ethyl

• Indication: For high-risk or very high-risk patients with hypertriglyceridemia (TG 135-499 mg/dL) despite statin therapy 6
• Cardiovascular benefit: Demonstrated in the REDUCE-IT trial 6

Treatment Algorithm for Statin-Intolerant Patients

1. First step: Ezetimibe 10 mg daily as monotherapy 6, 1

   • Assess LDL-C after 4-6 weeks 2
   • Expected reduction: 15-20% 3, 7

2. If LDL-C goal not achieved with ezetimibe alone:

   • For moderate-risk patients: Consider adding bile acid sequestrant 6, 1
   • For high/very high-risk patients: Add PCSK9 inhibitor 6
   • Alternative approach: Try low-dose statin (e.g., atorvastatin 10 mg twice weekly) with ezetimibe 5

3. For patients with mixed dyslipidemia:

   • Consider ezetimibe + fenofibrate combination 2

Practical Considerations

• Monitor liver enzymes as clinically indicated with ezetimibe use 2
• Ezetimibe has minimal drug interactions compared to other lipid-lowering agents 3, 7
• For patients with diabetes or metabolic syndrome, consider pitavastatin (if tolerated) + ezetimibe or bempedoic acid 6
• PCSK9 inhibitors are typically reserved for very high-risk patients due to cost and administration route 6

Common Pitfalls to Avoid

• Underestimating the cardiovascular benefit of modest LDL-C reduction with ezetimibe
• Failing to try ezetimibe before moving to more expensive therapies like PCSK9 inhibitors
• Not considering combination therapy with low-dose intermittent statins for truly statin-intolerant patients
• Overlooking the potential benefit of bile acid sequestrants in patients with diabetes due to their modest hypoglycemic effects 1